U.S. patent application number 11/274538 was filed with the patent office on 2007-05-17 for medical articles having enhanced therapeutic agent binding.
This patent application is currently assigned to Boston Scientific Scimed, Inc.. Invention is credited to Michael N. Helmus, Barron Tenney.
Application Number | 20070110786 11/274538 |
Document ID | / |
Family ID | 38041108 |
Filed Date | 2007-05-17 |
United States Patent
Application |
20070110786 |
Kind Code |
A1 |
Tenney; Barron ; et
al. |
May 17, 2007 |
Medical articles having enhanced therapeutic agent binding
Abstract
According to an aspect of the present invention, medical
articles are provided which comprise the following (a) a polymeric
region having a first charge, and (b) a charged therapeutic agent
having a second charge that is opposite in sign to that of the
first charge. In certain beneficial embodiments, the medical
articles are high surface area articles, for example, articles
formed using small diameter (e.g., 10 microns or less) fibers.
Inventors: |
Tenney; Barron; (Haverhill,
MA) ; Helmus; Michael N.; (Worcester, MA) |
Correspondence
Address: |
MAYER & WILLIAMS PC
251 NORTH AVENUE WEST
2ND FLOOR
WESTFIELD
NJ
07090
US
|
Assignee: |
Boston Scientific Scimed,
Inc.
|
Family ID: |
38041108 |
Appl. No.: |
11/274538 |
Filed: |
November 15, 2005 |
Current U.S.
Class: |
424/423 ;
514/44R |
Current CPC
Class: |
A61K 47/60 20170801;
A61K 47/645 20170801; A61L 2300/80 20130101; A61K 47/58 20170801;
A61L 27/54 20130101; A61L 31/10 20130101; A61L 31/14 20130101; A61L
2400/12 20130101; A61K 47/59 20170801; A61L 27/34 20130101; A61L
27/50 20130101; A61L 31/16 20130101 |
Class at
Publication: |
424/423 ;
514/044 |
International
Class: |
A61K 48/00 20060101
A61K048/00; A61F 2/02 20060101 A61F002/02 |
Claims
1. A medical article comprising (a) a fiber having a diameter of 10
microns or less, said fiber comprising a polymeric region having a
first charge, and (b) a charged therapeutic agent having a second
charge that is opposite in sign to that of said first charge that
is bound to said fiber.
2. The medical article of claim 1, wherein said medical article
comprises a plurality of fibers.
3. The medical article of claim 1, wherein said fiber comprises a
plurality of polymeric regions.
4. The medical article of claim 1, wherein a plurality of different
charged therapeutic agents are bound to said fiber.
5. The medical article of claim 1, wherein said polymeric region
extends throughout the diameter of said fiber.
6. The medical article of claim 1, wherein said polymeric region is
a coating layer.
7. The medical article of claim 1, wherein said polymeric region
comprises a nanotextured surface.
8. The medical article of claim 1, wherein said polymeric region
has a critical surface energy between 20 and 30 dynes/cm.
9. The medical article of claim 1, wherein polymers make up 75% or
more of said polymeric region.
10. The medical article of claim 1, wherein said fiber has a
diameter between 10 nm and 10 microns.
11. The medical article of claim 1, wherein said first charge is a
positive charge and said second charge is a negative charge.
12. The medical article of claim 11, wherein said charged
therapeutic agent is DNA.
13. The medical article of claim 1, wherein said first charge is a
negative charge and said second charge is a positive charge.
14. The medical article of claim 13, wherein said therapeutic agent
is selected from amiloride, digoxin, morphine, procainamide, and
quinine.
15. The medical article of claim 1, wherein said polymeric region
comprises a polyionic polymer.
16. The medical article of claim 15, wherein said polyionic polymer
is a polycationic polymer.
17. The medical article of claim 15, wherein said polyionic polymer
is a polyanionic polymer.
18. The medical article of claim 1, wherein a charged species
having said first charge is covalently attached to a surface of
said polymeric region.
19. The medical article of claim 18, wherein said charged species
is linked to said polymeric region using a linking agent.
20. The medical article of claim 18, wherein said charged species
is provided by chemical treatment.
21. The medical article of claim 20, wherein said polymeric region
is treated with an oxidizing or reducing agent.
22. The medical article of claim 20, wherein said surface comprises
sulfonate groups.
23. The medical article of claim 20, wherein said chemical
treatment comprises plasma treatment in the presence of a reactive
gas.
24. The medical article of claim 23, wherein said gas comprises
oxygen, carbon monoxide, carbon dioxide, ammonia, a mixture of
molecular hydrogen and molecular nitrogen, or an amine.
25. The medical article of claim 23, wherein said gas comprises an
unsaturated species that further comprises an acidic or basic
functional group.
26. The medical article of claim 1, wherein a charged species
having said first charge is non-covalently linked to a surface of
said polymeric region.
27. The medical article of claim 1, wherein said charged
therapeutic agent is selected from a therapeutic agent that is
inherently charged, a therapeutic agent that is covalently attached
to a charged molecule, a therapeutic agent that is non-covalently
attached to a charged molecule, a therapeutic agent that is
attached to or encapsulated within a charged particle, and a
combination thereof.
28. The medical article of claim 1, wherein the polymeric region
comprises a copolymer that comprises styrene and isobutylene.
29. The medical article of claim 28, wherein the copolymer
comprises a polyisobutylene block and a polystyrene block.
30. The medical article of claim 28, wherein the copolymer is a
polystyrene-polyisobutylene-polystyrene triblock copolymer.
31. The medical article of claim 28, wherein the copolymer is
sulfonated.
32. The medical article of claim 28, wherein said medical article
comprises a woven region comprising said fiber.
33. The medical article of claim 1, wherein said medical article
comprises a non-woven region comprising said fiber.
34. The medical article of claim 1, wherein said medical article is
a porous, tubular medical article.
35. The medical article of claim 1, wherein said medical article is
selected from hollow fibers for oxygenators, hernia repair patches,
gastrointestinal tract patches, uro-gynecological tract patches,
vascular access ports, fabric to join devices to human arteries,
wound dressings, membranes, anterior cruciate ligaments,
neurovascular aneurysm treatment articles, valve leaflets for heart
valves, valve leaflets for venous valves, stents, stent grafts,
gastrointestinal tract grafts, uro-gynecological tract grafts,
coronary vascular grafts, peripheral vascular grafts,
arterio-venous access grafts, embolic filters, and scaffolds for
tissue engineering.
36. The medical article of claim 1, wherein said medical article
comprises a region comprising said fiber, disposed over an
underlying medical device substrate.
37. The medical article of claim 36, wherein said medical device
substrate is a metallic stent.
Description
FIELD OF THE INVENTION
[0001] This invention relates to medical articles, and more
particularly to medical articles that contain one or more
therapeutic agents.
BACKGROUND OF THE INVENTION
[0002] The in vivo delivery of therapeutic agents to patients'
bodies is common in the practice of modern medicine. In vivo
delivery of therapeutic agents is often implemented using medical
devices that may be temporarily or permanently placed at a target
site within the body. These medical devices can be maintained, as
required, at their target sites for short or prolonged periods of
time, delivering therapeutic agents at the target sites.
[0003] In accordance with some delivery strategies, a therapeutic
agent is provided within or beneath a polymeric layer that is
associated with the medical device. Once the medical device is
placed at the desired location within a patient, the therapeutic
agent is released from the medical device with a profile that is
dependent, for example, upon the loading of the therapeutic agent
and upon the nature of the polymeric layer. In many such instances,
however, the therapeutic agent remains trapped within the medical
device and is thus of no benefit to the patient.
[0004] One solution to this problem is to dispose the therapeutic
agent at the surface of the medical device. However, the amount of
therapeutic agent that can be disposed at the surface is limited,
particularly for smooth, planar surfaces. Moreover, without
significant attractive forces between the therapeutic agent and the
surface, minimal agent may ultimately become bound to the surface
and/or the agent will be released prematurely in the body,
resulting in a loss in efficacy for the therapeutic agent.
[0005] These and other drawbacks are addressed by the present
invention.
SUMMARY OF THE INVENTION
[0006] According to an aspect of the present invention, medical
articles are provided which comprise the following (a) a polymeric
region having a first charge, and (b) a charged therapeutic agent
having a second charge that is opposite in sign to that of the
first charge. In certain beneficial embodiments, the medical
articles are high surface area articles, for example, articles
formed using small diameter (e.g., 10 microns or less) fibers.
[0007] An advantage of the present invention is that the amount of
therapeutic agent that is bound to the medical articles of the
present invention may be enhanced.
[0008] Another advantage of the present invention is that the
amount of therapeutic agent that is released prematurely may be
decreased.
[0009] These and other embodiments and advantages of the present
invention will become immediately apparent to those of ordinary
skill in the art upon review of the Detailed Description and Claims
to follow.
DETAILED DESCRIPTION OF THE INVENTION
[0010] According to an aspect of the present invention, medical
articles are provided which contain at least one polymeric region
and at least one therapeutic agent. The polymeric regions and
therapeutic agents selected for use in the articles of the present
invention are of opposite charge, thereby promoting electrostatic
binding between the therapeutic agent and the surface of the
polymeric region.
[0011] A positive charge may arise, for example, from the presence
of cationic moieties. Anionic moieties may also be present, so long
as the anionic moieties contribute less to the overall charge than
do the cationic moieties.
[0012] Conversely, a negative charge may arise, for example, from
the presence of anionic moieties. Cationic moieties may also be
present, so long as the cationic moieties contribute less to the
overall charge than do the anionic moieties.
[0013] The charge of a particular polymeric region or therapeutic
agent may change with the pH of its surrounding environment.
Consequently, the pH encountered by the polymeric region and the
therapeutic agent at the time of binding may be monitored and
controlled in some embodiments to optimize the charge differential
between the polymeric material and the therapeutic agent. In
certain embodiments, efforts are made to match the binding pH with
the physiological pH experienced by the medical article within the
body, for example, in order to enhance binding continuity from
environment to environment. On the other hand, in certain
embodiments, the physiological pH may differ substantially from the
binding pH, such that the therapeutic agent and/or the polymeric
region may become more charge neutral, or such that the charge of
the therapeutic agent and/or the polymeric region changes sign
(e.g., in the case of therapeutic agents or polymeric regions
having both acidic and basic functional groups), resulting in rapid
release of the therapeutic agent.
[0014] The present invention is applicable to a wide range of
medical articles including, for example, internal medical devices
(e.g., medical devices that are at least partially implantable,
insertable, etc.). Internal medical devices benefiting from the
various aspects and embodiments of the present invention are
numerous and may be selected, for example, from the following:
catheters (e.g., renal or vascular catheters such as balloon
catheters), balloons, guide wires, filters (e.g., vena cava
filters), stents (including coronary vascular stents, peripheral
vascular stents, cerebral, urethral, ureteral, biliary, tracheal,
gastrointestinal and esophageal stents), stent grafts, vascular
grafts, vascular access ports, embolization devices including
cerebral aneurysm filler coils (such as Guglilmi detachable coils
and various other metal coils), myocardial plugs, septal defect
closure devices, patches, pacemakers and pacemaker leads,
defibrillation leads and coils, left ventricular assist hearts and
pumps, total artificial hearts, heart valves, vascular valves,
tissue engineering scaffolds for in vivo tissue regeneration,
biopsy devices, as well as many other devices that are implanted or
inserted into the body and from which therapeutic agent is
released.
[0015] Polymeric regions for use in the various aspects and
embodiments of the present invention may be provided in a variety
of forms, including polymeric layers that are formed over all or
only a portion of an underlying medical article substrate,
polymeric regions that do not require an underlying substrate, such
as scaffolds and fibers, and so forth.
[0016] Layers can be provided over an underlying substrate at a
variety of locations, and in a variety of shapes. They may be
stacked on one another. Consequently, one can stack multiple layers
each having its own bound therapeutic agent, such that the
therapeutic agents emerge in series. As used herein a "layer" of a
given material is a region of that material whose thickness is
small compared to both its length and width. As used herein a layer
need not be planar, for example, taking on the contours of an
underlying substrate. Layers can be discontinuous (e.g.,
patterned). Terms such as "film," "layer" and "coating" may be used
interchangeably herein. Where polymeric layers are formed over all
or only a portion of an underlying substrate, the underlying
substrate may be formed from a variety of materials including
metallic materials and non-metallic materials such as ceramic
materials, carbon-based materials, silicon-based materials,
polymeric materials, and so forth.
[0017] Where fibers are employed, the polymer region may
correspond, for example, to the entire fiber or to a coating on the
fiber. Medical articles in accordance with the present invention
that are formed from fibers include two-dimensional structures
(e.g., patches) and three-dimensional structures (e.g., tubes),
which may be formed using any suitable fiber-based construction
technique including, for example, a variety of woven and non-woven
techniques. Examples of non-woven techniques include those
utilizing thermal fusion, fusion due to removal of residual
solvent, mechanical entanglement, chemical binding, adhesive
binding, and so forth. Moreover, the polymer region may correspond
to a fiber-containing region (e.g., a woven or non-woven
fiber-containing region) that is disposed over a substrate, for
example, a medical device substrate (e.g., a metallic stent
substrate such as a stainless steel or nitinol stent substrate),
among many other possibilities.
[0018] Specific examples of fiber-based medical articles include
hollow fibers for oxygenators, patches (including replacement
patches) such as patches for hernia repair and patches for the
gastrointestinal tract and the urogenital system, fabric to join
LVADs (left ventricular assist devices) and TAHs (total artificial
hearts) to human arteries, wound dressings, membranes, anterior
cruciate ligaments, neurovascular aneurysm treatment articles,
valve leaflets for heart valves and venous valves, grafts,
including large and small vascular grafts such as coronary artery
bypass grafts, peripheral vascular grafts and endovascular grafts,
stent grafts, grafts for the gastrointestinal tract and the
urogenital system, vascular access devices including vascular
access ports and arterio-venous access grafts (e.g., devices which
are utilized to give frequent arterial and/or venous access such as
for antibiotics, total parental nutrition, intravenous fluids,
blood transfusion, blood sampling, or arterio-venous access for
hemodialysis, and so forth), other tubular structures, for example,
biliary, urethral, ureteral and uterine tubular structures, embolic
filters, scaffolds for tissue engineering including cardiac tissue,
skin, mucosal and vascular tissue, and so forth.
[0019] Regardless of their overall form, polymeric regions suitable
for use in the present invention are beneficially high surface area
regions. For instance, where the polymeric regions are provided in
the form of fibers or fiber coatings, as a general rule (e.g.,
assuming no variation in surface texture), decreases in fiber
diameter will lead to increases in surface area of the polymer
regions. Thus, fibers selected for use in the present invention
include small diameter fibers, which have diameters that are less
than 10 microns (.mu.m), less than 1 micron, or even less than 500
nm (e.g., 10 nm to 25 nm to 50 nm to 100 nm to 250 nm to 500 nm).
Taking as an example a polymer having a density of 1 g/cm.sup.3, 1
gram of that polymer corresponds to 1 cubic centimeter of material.
For a smooth fiber, fiber volume is equal to .pi.r.sup.2L. For a 1
micron fiber, which has a radius of 0.5.times.10.sup.4 cm, 1
cm.sup.3 of polymer=.pi.(0.5.times.10.sup.4 cm).sup.2L, which
corresponds to a fiber length of 1.2732.times.10.sup.8 cm. The
surface area of this fiber (excluding end area, which is
insignificant) is .pi.dL=.pi.(10.sup.4 cm)(1.273.times.10.sup.8
cm)=4.times.10.sup.4 cm.sup.2, which corresponds to a specific
surface area of 4.times.10.sup.4 cm.sup.2/g. Please note that
surface area is inversely proportional to diameter. For example, a
10 micron fiber by this calculation has a specific surface area of
4.times.10.sup.3 cm.sup.2/g, whereas a 0.1 micron fiber has a
specific surface area of 4.times.10.sup.5 cm.sup.2/g. Hence,
specific surface areas for fibers in accordance with the present
invention may range, for example, from 10.sup.3 cm.sup.2/g to
10.sup.4 cm.sup.2/g to 10.sup.5 cm.sup.2/g, among other values.
[0020] In addition to decreasing material cross section (e.g.,
diameter, in the case of fibers), surface area may also be
increased through the creation of surface texture. In some
embodiments, the polymeric regions employed for the practice of the
present invention have nanotextured surfaces. Nanotextured surfaces
are those that contain surface nanofeatures, which are surface
features (e.g., raised features, depressed features, etc.) that
have at least one dimension (and often two or three dimensions)
less than 100 nm in length. As a specific example, it is noted that
a ridge or trench that is 10 nm wide, by 10 nm high/deep, by 1
micron long is nonetheless a nanostructure, as the term is used
herein, because it has at least one dimension (i.e., its width and
its height/depth), which is less than 100 nm in length. Of course,
nanotextured surfaces may also contain features that are not
nanofeatures. Beside ridges and trenches, other examples of surface
nanofeatures include hills, mesas/plateaus, terraces, surface
pores, and so forth.
[0021] A "polymeric region" is a region that contains polymers,
commonly at least 50 wt %, 75 wt %, 90 wt %, 95 wt % or even more,
polymers. As used herein, "polymers" are molecules that contain
multiple copies of one or more constitutional units, commonly
referred to as monomers, and typically containing from 5 to 10 to
25 to 50 to 100 to 500 to 1000 or more constitutional units. The
polymers may be, for example, homopolymers, which contain multiple
copies of a single constitutional unit, and/or copolymers, which
contain multiple copies of at least two dissimilar constitutional
units, which units may be present in any of a variety of
distributions including random, statistical, gradient, and periodic
(e.g., alternating) distributions. The polymers for use in the
present invention may have a variety of architectures, including
cyclic, linear and branched architectures. Branched architectures
include star-shaped architectures (e.g., architectures in which
three or more chains emanate from a single branch point), comb
architectures (e.g., architectures having a main chain and a
plurality of side chains) and dendritic architectures (e.g.,
arborescent and hyperbranched polymers), among others. "Block
copolymers" are polymers containing two or more differing polymer
chains, for example, selected from homopolymer chains and random
and periodic copolymer chains.
[0022] As noted above, polymeric regions in accordance with the
present invention may be negatively or positively charged, for
example, (a) by forming the polymeric regions using polymers that
are either inherently charged or are modified to possess a charge,
or (b) by modifying the polymeric regions to introduce a surface
charge after they are formed.
[0023] Examples of polymers that are inherently charged include
polyionic polymers that are polycationic and those that are
polyanionic at a relevant pH (e.g., the binding pH). Such polymers
typically have multiple (e.g., 5, 10, 25, 50, 100, or more,
frequently, many more) charged sites. They include polyacids,
polybases and polysalts, for example, polyelectrolytes, including
ionomers (polyelectrolytes in which a small but significant
proportion of the constitutional units carry charges). As indicated
above, polymers containing both cationic and anionic groups are
categorized herein as either polycationic polymers or polyanionic
polymers, depending on the relative amounts of anionic and cationic
groups possessed by the polymer.
[0024] Polycationic polymers suitable for the practice of the
invention may be natural or synthetic, they may be homopolymers or
copolymers, and they may be used singly or in blends. Polycationic
polymers for the practice of the present invention may be selected,
for example, from suitable homopolymers and copolymers that have or
are capable of having (e.g., via protenation or salt dissociation),
one or more of the following cationic groups: charged amino groups,
including charged primary (--NH.sub.3.sup.+), secondary and
tertiary amino groups, amidinium groups, guanidinium groups,
triazolium groups, imidazolium groups, imidazolinium groups,
pyridinium groups, sulfonium groups, including primary
(--SH.sub.2.sup.+) and secondary sulfonium groups, hydrosulfide
groups, phosphonium groups, including primary (--PH.sub.3.sup.+),
secondary, and tertiary phosphonium groups, isothiouronium groups,
nitrosyl groups, nitryl groups, tropilium groups, iodonium groups,
arsonium groups, antimonium groups, oxonium groups, and anilinium
groups, among others.
[0025] Specific examples of polycationic polymers may be selected,
for example, from suitable members of the following: polyamines,
including polyamidoamines, poly(amino methacrylates) including
poly(dialkylaminoalkyl methacrylates) such as
poly(dimethylaminoethyl methacrylate) and poly(diethylaminoethyl
methacrylate), polyvinylamines, polyvinylpyridines including
quaternary polyvinylpyridines such as
poly(N-ethyl-4-vinylpyridine), poly(vinylbenzyltrimethylamines),
polyallylamines and poly(diallyldialklylamines) such as
poly(diallyldimethylammonium chloride), spermine, spermidine,
hexadimethrene bromide (polybrene), polyimines including
polyalkyleneimines such as polyethyleneimines, polypropyleneimines
and ethoxylated polyethyleneimines, basic peptides and proteins,
including histone polypeptides and polymers containing lysine,
arginine, ornithine and combinations thereof including
poly-L-lysine, poly-D-lysine, poly-L,D-lysine, poly-L-arginine,
poly-D-arginine, poly-D,L-arginine, poly-L-ornithine,
poly-D-ornithine, poly-L,D-ornithine, gelatin, albumin, protamine,
and polycationic polysaccharides such as cationic starch and
chitosan, among others.
[0026] As with polycationic polymers, polyanionic polymers suitable
for the practice of the invention may be natural or synthetic, they
may be homopolymers or copolymers, and they may be used singly or
in blends. Polyanionic polymers for the practice of the present
invention may be selected, for example, from suitable homopolymers
and copolymers that have or are capable of having (e.g., via proton
donation or salt dissociation), one or more of the following
anionic groups: phosphate groups, sulfate groups, sulfonate groups,
phosphonates groups and carboxylate groups, among others.
[0027] Specific examples of polyanionic polymers may be selected,
for example, from suitable members of the following: (a)
polysulfonates such as polyvinylsulfonates, poly(styrenesulfonates)
such as poly(sodium styrenesulfonate) (PSS), sulfonated
poly(tetrafluoroethylene), sulfonated polymers such as those
described in U.S. Pat. No. 5,840,387, including sulfonated
styrene-ethylene/butylene-styrene triblock copolymers, sulfonated
styrenic homopolymers and copolymer such as a sulfonated versions
of the polystyrene-polyolefin copolymers described in U.S. Pat. No.
6,545,097 to Pinchuk et al., which polymers may be sulfonated, for
example, using the processes described in U.S. Pat. No. 5,840,387
and U.S. Pat. No. 5,468,574, as well as sulfonated versions of
various other homopolymers and copolymers, (b) polycarboxylates
such as acrylic acid polymers and salts thereof (e.g., ammonium,
potassium, sodium, and so forth salts), for instance, those
available from Atofina and Polysciences Inc., methacrylic acid
polymers and salts thereof (e.g., EUDRAGIT, a methacrylic acid and
ethylacrylate copolymer), carboxymethylcellulose,
carboxymethylamylose and carboxylic acid derivatives of various
other polymers, polyanionic peptides and proteins such as glutamic
acid polymers and copolymers, aspartic acid polymers and
copolymers, and gelatin, (c) polyphosphates such as phosphoric acid
derivatives of various polymers, (d) polyphosphonates such as
polyvinylphosphonates, (e) polysulfates such as polyvinylsulfates,
and so forth.
[0028] Additional examples include sulfated and non-sulfated
polysaccharides, including sulfated and non-sulfated
glycosaminoglycans as well as species containing the same such as
proteoglycans, for instance, selected from heparin, heparin
sulfate, chondroitin sulfate, keratan sulfate, dermatan sulfate,
hyaluronan, bamacan, perlecan, biglycan, fibromodulin, aggrecan,
decorin, mucin, carrageenan, polymers and copolymers of uronic
acids such as mannuronic acid, galatcuronic acid and guluronic
acid, for example, alginic acid (a copolymer of beta-D-mannuronic
acid and alpha-L-guluronic acid). Such charged polysaccharide
species may be attached to a cell adhesion peptide, a protein, a
protein fragment and/or a biocompatible polymer, as described in
Ser. No. 10/781,932.
[0029] To the extent that the polymers of choice for use in the
polymeric regions of the invention do not inherently have a charge,
charged groups may nonetheless be introduced.
[0030] For example, as seen above in conjunction with sulfonated
polymers, polymers including styrenic and other polymers may be
chemically treated with various reagents, including reducing agents
and oxidizing agents (e.g., sulfur trioxide for sulfonate
formation), which modify their surfaces so as to provide them
charged groups, such as such as amino, phosphate, sulfate,
sulfonate, phosphonates and carboxylate groups.
[0031] As another example, charged groups may be introduced by
covalently linking (grafting) charged species to the polymers.
Examples of charged species include, for example, species
containing the cationic and anionic groups discussed above.
Covalent linkage may proceeds via a number of chemically reactive
functional groups, including amino, hydroxyl, sulthydryl, carboxyl,
and carbonyl groups, as well as carbohydrate groups, vicinal diols,
thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl
and phenolic groups, among others.
[0032] Covalent coupling of charged species to polymers, each
having reactive functional groups, may be carried out, for example,
by direct reaction between such functional groups, or more
typically by using linking agents that contain reactive moieties
capable of reaction with such functional groups. Specific examples
of commonly used linking agents include glutaraldehyde,
diisocyanates, diiosothiocyanates, bis(hydroxysuccinimide)esters,
maleimidehydroxysuccinimide esters, carbodiimides,
N,N'-carbonyldiimidazole imidoesters, and difluorobenzene
derivatives, among others. One ordinarily skilled in the art will
recognize that any number of other coupling agents may be used
depending on the functional groups present. In some embodiments, it
is desirable for the polymer and the charged compound to have
differing functional groups, so as to avoid self-coupling
reactions. Functional groups present on the charged species and/or
polymeric region may be converted, as desired, into other
functional groups prior to reaction, e.g. to confer additional
reactivity or selectivity. Further information on covalent coupling
may be found, for example, in U.S. Pub. No. 2005/0002865, which is
incorporated by reference.
[0033] As another example, charged groups may be introduced by
non-covalently linking charged compounds to the polymers, for
example, based on hydrogen bonding (e.g., multiple hydrogen bonds)
between the polymers and with the charged compounds, based on the
formation of complexes and/or coordinative bonds with charged
species, or other strong non-covalent interaction.
[0034] As noted above, in certain embodiments, charge may be
provided after the polymeric region is formed. For example,
techniques such as those described above (e.g., chemical treatment,
covalent or non-covalent coupling of charged species, etc.) may be
performed on the polymeric region in order to provide charged
groups.
[0035] Other techniques for providing surface charge include
techniques whereby a polymeric region is treated with a reactive
plasma. For example, gas discharge techniques have been used to
functionalize polymer surfaces. Surface modification is obtained by
exposing the surface to a partially ionized gas (i.e., to a
plasma). Two types of processes are frequently described, depending
on the operating pressure: corona discharge techniques (which are
conducted at atmospheric pressure) and glow discharge techniques
(which are conducted at reduced pressure). Because the plasma phase
consists of a wide spectrum of reactive species (electrons, ions,
etc.) these techniques have been used widely for functionalization
of polymer surfaces.
[0036] Glow discharge techniques may be preferred over corona
discharge techniques in certain embodiments, because the shape of
the object to be treated is of minor importance during glow
discharge processes. Moreover, glow discharge techniques are
usually either operated in an etching or in a depositing mode,
depending on the gas used, whereas corona discharge techniques are
usually operated in an etching mode. A commonly employed glow
discharge technique is radio-frequency glow discharge (RFGD).
[0037] Plasma treatment processes have been widely used to etch,
crosslink and/or functionalize surfaces, with these processes
occurring simultaneously at a polymer surface that is exposed to a
discharge of a non-polymerizable gas. The gas that is used
primarily determines which of these processes is dominant. When
gases like carbon monoxide (CO), carbon dioxide (CO.sub.2), or
oxygen (O.sub.2) are used, functionalization with --COOH groups
(which donate protons to form anionic groups) is commonly observed.
When gases like ammonia, a propyl amine, or N.sub.2/H.sub.2 are
employed, --NH.sub.2 groups (which accept protons to form cationic
groups) are commonly formed.
[0038] Functional group containing surfaces may also be obtained
using plasma polymerization processes in which "monomers" are
employed that contain functional groups. Allylamine (which produces
--NH.sub.2 groups) and acrylic acid (which produces --COOH groups)
have been used for this purpose. By using a second feed gas
(generally a non-polymerizable gas) in combination with the
unsaturated monomer, it is possible to incorporate this second
species in the plasma deposited layer. Examples of gas pairs
include allylamine/NH.sub.3 (which leads to enhanced production of
--NH.sub.2 groups) and acrylic acid/CO.sub.2 (which leads to
enhanced production of --COOH groups).
[0039] The above and further information may be found, for example,
in "Functionalization of Polymer Surfaces," Europlasma Technical
Paper, May 8, 2004 and in U.S. patent application Publication No.
2003/0236323.
[0040] In certain embodiments, charged polymeric regions in
accordance with the invention are in the form of charged polymeric
coatings. In these embodiments, the polymeric coatings may contain
one or more polymer species that is charged (e.g., inherently or
otherwise), or the polymeric coating may be processed to provide it
with a surface charge (e.g., by chemical treatment, by covalent or
non-covalent coupling of charged species, by plasma treatment), as
detailed above.
[0041] Regardless of the method by which the polymeric region is
created and provided with a charge, it is beneficial in certain
embodiments to provide the polymeric region with a critical surface
energy between 20 and 30 dynes/cm. Surfaces having a critical
surface energy between 20-30 dynes/cm have been shown in work by
Dr. Robert Baier and others to provide enhanced biocompatibility,
including enhanced thromboresistance. See, e.g., Baier R E,
Meenaghan M A, Hartman L C, Wirth J E, Flynn H E, Meyer A E,
Natiella J R, Carter J M, "Implant Surface Characteristics and
Tissue Interaction", J Oral Implantol, 1988, 13(4), 594-606; Robert
Baier, Joseph Natiella, Anne Meyer, John Carter, "Importance of
Implant Surface Preparation for Biomaterials with Different
Intrinsic Properties in Tissue Integration in Oral and
Maxillofacial Reconstruction"; Current Clinical Practice Series
#29, 1986; Robert Baier, Joseph Natiella, Anne Meyer, John Carter,
Formalik, M. S., Tumbull, T., "Surface Phenomena in In Vivo
Environments. Applications of Materials Sciences to the Practice of
Implant Orthopedic Surgery", NATO Advanced Study Institute, Costa
Del Sol, Spain, 1984; Baier R E, Meyer A E, Natiella J R, Natiella
R R, Carter J M, "Surface properties determine bioadhesive
outcomes: methods and results", J Biomed Mater Res, 1984, 18(4),
327-355; Joseph Natiella, Robert Baier, John Carter, Anne Meyer,
Meenaghan, M. A., Flynn, H. E., "Differences in Host Tissue
Reactions to Surface-Modified Dental Implants", 185th ACS National
Meeting, American Chemical Society, 1983.
[0042] In this regard, methods are known for measuring critical
surface energy. For example, contact angle methods can be used to
produce Zisman plots for calculating critical surface tensions. For
further information on measuring critical surface energy, see,
e.g., Zisman, W. A., "Relation of the equilibrium contact angle to
liquid and solid constitution," Adv. Chem. Ser. 43, 1964, pp. 1-51;
Baier R. E., Shiafrin E. G., Zisman, W. A., "Adhesion: Mechanisms
that assist or impede it," Science, 162: 1360-1368, 1968; Fowkes,
F. M., "Contact angle, wettability and adhesion," Washington D.C.,
Advances in Chemistry, vol. 43, 1964, p. 1, Souheng Wu, Polymer
Interface and Adhesion, Marcel Dekker, 1982, Chapter 5, pp.
169-212. Hence, various polymer surfaces may be tested, if desired,
to determine whether or not those surfaces have a critical surface
energy within the above criteria.
[0043] Numerous techniques are available for forming polymeric
regions in accordance with the present invention. For example,
wherein one or more polymers within the polymeric regions have
thermoplastic characteristics, and so long as the polymers and any
other optional supplemental materials are sufficiently stable under
processing conditions, a variety of standard thermoplastic
processing techniques may be used to form the polymeric regions,
including compression molding, injection molding, blow molding,
spinning, vacuum forming, calendaring, extrusion into sheets,
fibers, rods, tubes and other cross-sectional profiles of various
lengths, and coextrusion into multilayered structures. Using these
and other thermoplastic processing techniques, entire medical
articles or portions thereof can be made.
[0044] In other embodiments, solvent-based techniques may be used
to form polymeric regions in accordance with the present invention.
Using these techniques, polymeric regions may be formed by first
providing solutions that contain the one or more polymers of
interest (and any other optional supplemental materials to be
processed), and subsequently removing the solvents to form the
polymeric regions. The solvents that are ultimately selected will
contain one or more solvent species, which are generally selected
based on their ability to dissolve the materials that form the
polymeric region, as well as other factors, including drying rate,
surface tension, etc. Solvent-based techniques include, but are not
limited to, solvent casting techniques, spin coating techniques,
web coating techniques, fiber spinning techniques, solvent spraying
techniques, dipping techniques, techniques involving coating via
mechanical suspension including air suspension, ink jet techniques,
electrostatic techniques, and combinations of these processes.
[0045] In some embodiments of the invention, a solution (where
solvent-based processing is employed) or a melt (where
thermoplastic processing is employed) is applied to a substrate to
form a polymeric region. For example, the substrate can correspond
to all or a portion of an implantable or insertable medical device
to which a polymeric region is applied. The substrate can also be,
for example, a template, such as a mold, from which the polymeric
region is removed after solidification. In other embodiments, for
example, extrusion and co-extrusion techniques, one or more
polymeric regions are formed without the aid of a substrate.
[0046] Taking fibers as a specific example, where employed, they
may be made by any suitable fiber forming technique, including melt
spinning, dry spinning and wet spinning. These processes typically
employ extrusion nozzles having one or more orifices, called jets
or spinnerets. Fibers having a variety of cross-sectional shapes
can be formed, depending upon the shape of the orifice(s) in the
spinning die. Some examples of fiber cross-sections include
circular, hexagonal, rectangular, triangular, oval, multi-lobed,
and annular (hollow) cross-sections. In melt spinning, the polymer
compound is heated to melt temperature. In wet and dry spinning the
polymer is dissolved in a solvent prior to extrusion, and the
extrudate is subjected to conditions whereby the solvent is
evaporated, for example, by exposure to a vacuum or heated
atmosphere (e.g., air) which removes the solvent by evaporation. In
wet spinning the jet or spinneret is immersed in a liquid, and as
the extrudate emerges, it precipitates from solution and
solidifies. Regardless of the technique, the resulting fiber is
typically taken up on a rotating mandrel or another take-up device.
During take up, the fiber may be stretched to orient the polymer
molecules.
[0047] In accordance with certain embodiments of the present
invention, a dry spinning technique is employed in which a
styrene-isobutylene copolymer containing solution is fed (e.g.,
using a metering pump such as a syringe pump) through one or more
fine orifices (e.g., those found in a dry spinning die, or
spinneret). Further details regarding dry spinning of
styrene-isobutylene copolymers, may be found in copending, commonly
assigned U.S. Ser. No. 10/801,228.
[0048] As indicated above, fibers may be formed into two- and
three-dimensional medical articles. One particularly beneficial
method for forming porous tubular three-dimensional structures from
fibers is described in U.S. Pat. No. 4,475,972 to Wong, the
disclosure of which is hereby incorporated by reference, in which
these articles are made by a procedure in which fibers are wound on
a mandrel and overlying fiber portions are simultaneously bonded
with underlying fiber portions. For instance, a polymer solution
may be extruded from a spinneret, thereby forming a plurality of
filaments which are wound onto a rotating mandrel, as the spinneret
reciprocates relative to the mandrel. The drying parameters (e.g.,
drying environment, solution temperature and concentration,
spinneret-to-mandrel distance, etc.) are controlled such that some
residual solvent remains in the filaments as they are wrapped upon
the mandrel. Upon further evaporation of the solvent, the
overlapping fibers on the mandrel become bonded to each other.
[0049] As discussed in detail above, fibers may be provided with
charges via a variety of techniques, including forming the fibers
using charged polymers (e.g., those that are inherently charged or
are provided with a charge before fiber formation) or by treating
the fiber subsequent to its formation (e.g., by chemical treatment
with a species that produces charged groups such as oxidizing and
reducing agents, by covalent or non-covalent coupling of charged
species, by plasma treatment, etc.), for example, either before or
after being formed into a two- or three-dimensional article. For
instance, the styrene-isobutylene copolymer described in commonly
assigned U.S. Ser. No. 10/801,228 may be provided with a charge
before fiber spinning (e.g., by sulfonation, etc.) or after fiber
spinning (e.g., by plasma treatment, sulfonation, etc.).
[0050] An advantage to providing medical articles with charged
polymeric regions is that, by selecting a charged therapeutic agent
of opposite charge, binding between the polymeric region and the
therapeutic agent may be enhanced. "Therapeutic agents," drugs,"
"bioactive agents" "pharmaceuticals," "pharmaceutically active
agents", and other related terms may be used interchangeably herein
and include genetic and non-genetic therapeutic agents as well as
cells. Therapeutic agents may be used singly or in combination.
[0051] A wide range of therapeutic agent loadings can be used in
conjunction with the devices of the present invention, with the
pharmaceutically effective amount being readily determined by those
of ordinary skill in the art and ultimately depending, for example,
upon the condition to be treated, the nature of the therapeutic
agent itself, the tissue into which the dosage form is introduced,
and so forth.
[0052] Exemplary non-genetic biologically active agents for use in
connection with the present invention include: (a) anti-thrombotic
agents such as heparin, heparin derivatives, urokinase, and PPack
(dextrophenylalanine proline arginine chloromethylketone); (b)
anti-inflammatory agents such as dexamethasone, prednisolone,
corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;
(c) antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promotors; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, bifunctional molecules consisting of a growth
factor and a cytotoxin, bifunctional molecules consisting of an
antibody and a cytotoxin; (h) protein kinase and tyrosine kinase
inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i)
prostacyclin analogs; (j) cholesterol-lowering agents; (k)
angiopoietins; (l) antimicrobial agents such as triclosan,
cephalosporins, antimicrobial peptides such as magainins,
aminoglycosides and nitrofurantoin; (m) cytotoxic agents,
cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; (o) agents that interfere with endogenous
vasoactive mechanisms, (p) inhibitors of leukocyte recruitment,
such as monoclonal antibodies; (q) cytokines; (r) hormones; (s)
inhibitors of HSP 90 protein (i.e., Heat Shock Protein, which is a
molecular chaperone or housekeeping protein and is needed for the
stability and function of other client proteins/signal transduction
proteins responsible for growth and survival of cells) including
geldanamycin, (t) beta-blockers, (u) bARKct inhibitors, (v)
phospholamban inhibitors, (w) Serca 2 gene/protein, (x) immune
response modifiers including aminoquizolines, for instance,
imidazoquinolines such as resiquimod and imiquimod, (y) human
apolioproteins (e.g., AI, AII, AIII, AIV, AV, etc.).
[0053] Some preferred non-genetic therapeutic agents include
paclitaxel (including particulate forms thereof, for instance,
protein-bound paclitaxel particles such as albumin-bound paclitaxel
nanoparticles, e.g., ABRAXANE), sirolimus, everolimus, tacrolimus,
Epo D, dexamethasone, estradiol, halofuginone, cilostazole,
geldanamycin, ABT-578 (Abbott Laboratories), trapidil, liprostin,
Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel, and
Ridogrel, beta-blockers, bARKct inhibitors, phospholamban
inhibitors, Serca 2 gene/protein, imiquimod, human apolioproteins
(e.g., AI-AV), growth factors (e.g., VEGF-2), as well a derivatives
of the forgoing, among others.
[0054] Exemplary genetic biologically active agents for use in
connection with the present invention include anti-sense DNA and
RNA as well as DNA coding for: (a) anti-sense RNA, (b) tRNA or rRNA
to replace defective or deficient endogenous molecules, (c)
angiogenic factors including growth factors such as acidic and
basic fibroblast growth factors, vascular endothelial growth
factor, epidermal growth factor, transforming growth factor .alpha.
and .beta., platelet-derived endothelial growth factor,
platelet-derived growth factor, tumor necrosis factor .alpha.,
hepatocyte growth factor and insulin-like growth factor, (d) cell
cycle inhibitors including CD inhibitors, and (e) thymidine kinase
("TK") and other agents useful for interfering with cell
proliferation. Also of interest is DNA encoding for the family of
bone morphogenic proteins ("BMP's"), including BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11,
BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred
BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These
dimeric proteins can be provided as homodimers, heterodimers, or
combinations thereof, alone or together with other molecules.
Alternatively, or in addition, molecules capable of inducing an
upstream or downstream effect of a BMP can be provided. Such
molecules include any of the "hedgehog" proteins, or the DNA's
encoding them.
[0055] Vectors for delivery of genetic therapeutic agents include
viral vectors such as adenoviruses, gutted adenoviruses,
adeno-associated virus, retroviruses, alpha virus (Semliki Forest,
Sindbis, etc.), lentiviruses, herpes simplex virus, replication
competent viruses (e.g., ONYX-015) and hybrid vectors; and
non-viral vectors such as artificial chromosomes and
mini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic
polymers (e.g., polyethyleneimine, polyethyleneimine (PEI)), graft
copolymers (e.g., polyether-PEI and polyethylene oxide-PEI),
neutral polymers PVP, SP1017 (SUPRATEK), lipids such as cationic
lipids, liposomes, lipoplexes, nanoparticles, or microparticles,
with and without targeting sequences such as the protein
transduction domain (PTD).
[0056] Cells for use in connection with the present invention
include cells of human origin (autologous or allogeneic), including
whole bone marrow, bone marrow derived mono-nuclear cells,
progenitor cells (e.g., endothelial progenitor cells), stem cells
(e.g., mesenchymal, hematopoietic, neuronal), pluripotent stem
cells, fibroblasts, myoblasts, satellite cells, pericytes,
cardiomyocytes, skeletal myocytes or macrophage, or from an animal,
bacterial or fungal source (xenogeneic), which can be genetically
engineered, if desired, to deliver proteins of interest.
[0057] Numerous biologically active agents, not necessarily
exclusive of those listed above, have been identified as candidates
for vascular treatment regimens, for example, as agents targeting
restenosis. Such agents are useful for the practice of the present
invention and include one or more of the following: (a) Ca-channel
blockers including benzothiazapines such as diltiazem and
clentiazem, dihydropyridines such as nifedipine, amlodipine and
nicardapine, and phenylalkylamines such as verapamil, (b) serotonin
pathway modulators including: 5-HT antagonists such as ketanserin
and naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/Guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) Angiotensin Converting Enzyme (ACE) inhibitors such
as cilazapril, fosinopril and enalapril, (h) ATII-receptor
antagonists such as saralasin and losartin, (i) platelet adhesion
inhibitors such as albumin and polyethylene oxide, (j) platelet
aggregation inhibitors including cilostazole, aspirin and
thienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa
inhibitors such as abciximab, epitifibatide and tirofiban, (k)
coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (l) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (o) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, fluvastatin, simvastatin and cerivastatin,
(u) fish oils and omega-3-fatty acids, (v) free-radical
scavengers/antioxidants such as probucol, vitamins C and E,
ebselen, trans-retinoic acid and SOD mimics, (w) agents affecting
various growth factors including FGF pathway agents such as bFGF
antibodies and chimeric fusion proteins, PDGF receptor antagonists
such as trapidil, IGF pathway agents including somatostatin analogs
such as angiopeptin and ocreotide, TGF-.beta. pathway agents such
as polyanionic agents (heparin, fucoidin), decorin, and TGF-.beta.
antibodies, EGF pathway agents such as EGF antibodies, receptor
antagonists and chimeric fusion proteins, TNF-.alpha. pathway
agents such as thalidomide and analogs thereof, Thromboxane A2
(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben
and ridogrel, as well as protein tyrosine kinase inhibitors such as
tyrphostin, genistein and quinoxaline derivatives, (x) MMP pathway
inhibitors such as marimastat, ilomastat and metastat, (y) cell
motility inhibitors such as cytochalasin B, (z)
antiproliferative/antineoplastic agents including antimetabolites
such as purine analogs (e.g., 6-mercaptopurine or cladribine, which
is a chlorinated purine nucleoside analog), pyrimidine analogs
(e.g., cytarabine and 5-fluorouracil) and methotrexate, nitrogen
mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g.,
daunorubicin, doxorubicin), nitrosoureas, cisplatin, agents
affecting microtubule dynamics (e.g., vinblastine, vincristine,
colchicine, Epo D, paclitaxel and epothilone), caspase activators,
proteasome inhibitors, angiogenesis inhibitors (e.g., endostatin,
angiostatin and squalamine), rapamycin, cerivastatin, flavopiridol
and suramin, (aa) matrix deposition/organization pathway inhibitors
such as halofuginone or other quinazolinone derivatives and
tranilast, (bb) endothelialization facilitators such as VEGF and
RGD peptide, and (cc) blood rheology modulators such as
pentoxifylline.
[0058] Numerous additional biologically active agents useful for
the practice of the present invention are also disclosed in U.S.
Pat. No. 5,733,925 assigned to NeoRx Corporation, the entire
disclosure of which is incorporated by reference.
[0059] Therapeutic agents for use in the present invention have an
associated charge. For example, a therapeutic agent may have an
associated charge because it is inherently charged (e.g., because
it has acidic and/or or basic groups, which may be in salt form). A
few examples of inherently charged cationic therapeutic agents
include amiloride, digoxin, morphine, procainamide, and quinine,
among many others. Examples of anionic therapeutic agents include
DNA, among many others.
[0060] As another example, a therapeutic agent may have an
associated charge because it has been modified to carry a charge,
for example, by covalently or non-covalently coupling a charged
species to the therapeutic agent.
[0061] For instance, various cationic forms of paclitaxel are
known, including paclitaxel methylpyridinium mesylate and
paclitaxel conjugated with N-2-hydroxypropyl methyl amide, as are
various anionic forms of paclitaxel, including
paclitaxel-poly(1-glutamic acid), paclitaxel-poly(1-glutamic
acid)-PEO. In addition to these, U.S. Pat. No. 6,730,699, which is
incorporated by reference in its entirety, also describes
paclitaxel conjugated to various other charged polymers including
poly(d-glutamic acid), poly(dl-glutamic acid), poly(1-aspartic
acid), poly(d-aspartic acid), poly(dl-aspartic acid),
poly(1-lysine), poly(d-lysine), poly(dl-lysine), copolymers of the
above listed polyamino acids with polyethylene glycol,
polycaprolactone, polyglycolic acid and polylactic acid, as well as
poly(2-hydroxyethyl 1-glutamine), chitosan, carboxymethyl dextran,
hyaluronic acid, human serum albumin and alginic acid. Still other
anionic forms of paclitaxel include carboxylated forms such as
1'-malyl paclitaxel sodium salt (see, e.g. E. W. DAmen et al.,
"Paclitaxel esters of malic acid as prodrugs with improved water
solubility," Bioorg Med. Chem., 2000 Feb., 8(2), pp. 427-32), which
is incorporated by reference in its entirety.
[0062] As yet another example, a therapeutic agent may have an
associated charge because it is attached to or encapsulated within
a charged particle, for example, a charged nanoparticle (i.e., a
charged particle having a cross-sectional dimension of 100 nm or
less, for example, a spherical particle or a rod-shaped particle
having a diameter of 100 nm or less) such as a nanocapsule or a
charged micelle, among others.
[0063] Charged nanoparticles may be formed, for example, from
polycationic polymers and polyanionic polymers such as those
described above. Specific examples of charged nanoparticles include
nanocapsules that contain alternating layers of (a) a polyanion,
for example, poly(L-glutamic acid) and (b) a polycation, for
example, poly(L-lysine). If desired a charged or uncharged
therapeutic agent may be provided within the core of the
nanocapsule. For example, see I. L. Radtchenko et al., "A novel
method for encapsulation of poorly water-soluble drugs:
precipitation in polyelectrolyte multilayer shells," International
Journal of Pharmaceutics, 242 (2002) 219-223 which is incorporated
by reference in its entirety. Charged therapeutic agent (e.g.,
paclitaxel conjugated to a polycation such as poly-L-lysine or a
polyanion such as poly-L-glutamic acid, among many others) may also
be provided within one or more of the layers of the
nanocapsule.
[0064] Further specific examples of charged particles include
charged micelles. For example, poly(ethylene
oxide)-block-poly(amino acids) may form charged micelles for drug
delivery.
[0065] Polymeric regions in accordance with the present invention
may be loaded with therapeutic agents, for example, at various
points after their formation. For example, taking fibrous articles
as an example, therapeutic agent loading may occur after fiber
formation or after the fiber is shaped into a medical article
(e.g., by a woven process, a non-woven process, etc.). Loading may
be conducted, for example, by exposing polymeric regions and
therapeutic agents of opposite charge to one another. For example,
the charged polymeric regions and therapeutic agents may be exposed
to one another in an aqueous solution at a pH where the therapeutic
agent and the polymeric region and have opposite charges.
[0066] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
* * * * *